Growth Hormone Deficiency (GHD) includes a group of different pathologies all with a failure or reduction of growth hormone (GH) secretion. GHD may occur by itself or in combination with other pituitary hormone deficiencies. It may be congenital or acquired as a result of trauma, infiltrations, tumour or radiation therapy. Despite the large number of possible aetiologies, most children have idiopathic GHD. Depending on the criteria for diagnosis, the incidence of short stature associated with severe childhood GHD has been estimated to range between 1:4000 to 1:10000 live children in several studies (P C Sizonenko et al., Growth Horm IGF Res 2001; 11 (3):137-165).
Postnatal growth of children with GHD differs according to aetiology. Genetic deficiency of GHD causes progressive slowing of growth following normal growth in the first months of life. Growth failure is the major presenting sign of GHD in children, and lack of GH therapy in the case of severe GHD leads to very short stature in adulthood (GH Research Society, J. Clin. Endocrinol Metabol 2000; 85 (11): 3990-3993).
Turner (or Ullrich-Turner) syndrome (TS) is a chromosomal abnormality characterized by the absence of the entire chromosome X or a deletion within that chromosome. TS affects one in 1,500 to 2,500 live-born females. Short stature and reduced final height are observed in 95% of girls with TS. The average difference between mean adult height of normal women and that of TS adults is of 20 cm (Park E. et al, Pediatr Res 1983; 17:1-7). Reduced final height is due to a decline in height velocity after the age of 5 or 6 years (relative to unaffected girls) and to the absence of a pubertal growth spurt (Brook CGD et al., Arch Dis Child 1974; 49:789-795) due to the lack of the normal increase in GH secretion observed during puberty. The short stature in TS is not attributable to deficient secretions of GH or insulin-like growth factor I (IGF-I) (Cuttlet L et al., J Clin Endocrinol Metab 1985; 60:1087-1092), but a decreased amplitude and frequency of GH pulses have been reported after the age of 8 years in these patients (Ross J L et al., J Pediatr 1985; 106:202-206).
Recombinant DNA-derived human growth hormone (GH) is the only drug approved specifically for treatment of childhood growth failure and short stature, such as GHD, SGA (Small for Gestational Age) and TS. Current dose regimens for childhood GH therapy are based on body weight and are derived primarily from empirical experience. The response to GH treatment, short-term as well as long-term, displays considerable inter-individual variability. This is particularly evident for the endpoint of paediatric GH administration, i.e. the growth response, which varies significantly in subjects with Turner syndrome, but is also pronounced in children who are affected by GHD.
This variability can be investigated at two different levels. First, at the phenotype level, by assessing the individual growth response to GH administration by means of the biological markers of GH action commonly used in the clinical management of short stature subjects. Secondly, at the genotype level, which can be investigated by identifying the genetic factors responsible for the phenotypic variation of the response to GH intervention.
Growth prediction models attempt to predict the individual response to growth hormone treatment based on either pre-treatment characteristics or response after a short period of growth hormone administration in comparison to the group response. Pre-treatment parameters used in existing prediction models for idiopathic GHD and Turner Syndrome children receiving GH therapy include auxological criteria, indices of endogenous GH secretion, biological markers of GH action such as insulin-like growth factors (IGF) and their binding proteins (IGFBP), and bone turnover markers.
Ranke at al. (J Clin Endocrinol Metab 1999; 84 (4):1174-1183) proposed a prediction model for first-year growth response in prepubertal GHD children using auxological criteria, peak GH values in GH stimulation tests and height velocity (HV) response. The data analysis suggested that the first year HV was negatively correlated with age and height standard deviation score (HSDS) and positively correlated with birth weight, weight at beginning of therapy, GH dose, frequency of injection, target HSDS, and the peak GH response to a stimulation test. Cole et al. (Arch Dis Child 2004; 89:1024-1027) reported that GH stimulation test result, although not a gold standard for diagnosis, is a valuable predictor of growth in the first year of treatment. Blethen et al (J Clin Endocrinol Metab 1993; 76 (3):574-579) reported that the initial response to GH therapy may be predicted by age, degree of GHD, weight adjusted for height, GH dose, injection frequency, and mid-parental height. The Ranke model was extended to examine second-, third- and fourth-year growth response, and has demonstrated that first-year height velocity is the most important predictor of subsequent growth. Overall, the model could explain 61% of the growth response variability during the first year of GH treatment. A similar model, based on auxological parameters, could explain 46% of the growth response to GH treatment in subjects with TS (Ranke et al. J Clin Endocrinol Metab 2000; 85 (11):4212-4218).
Growth prediction models have variable predictive power, and although suitable to describe the variance within a defined cohort of patients, they fail to explain the total variance of the GH response. The major contributors to the remaining variance are conceivably genetic determinants.
There is thus a need to define a set of biological markers and genetic/genomic markers associated with short term GH treatment response that could complement the previously identified parameters to increase the accuracy with which response to GH treatment could be predicted.